Severe Acute Respiratory Syndrome (SARS) is a recently recognized epidemic disease characterized by significant morbidity and nearly 10% mortality. The etiologic agent is an enveloped RNA coronavirus. Coronaviruses are prevalent in nature and current findings suggest that the SARS eoronavirus entered the human population from animal reservoirs. Numerous studies have shown that the surface-exposed spike glycoproteins involved in coronavirus binding to host cells are critical factors in epidemiology and pathogenicity. Thus, it is likely that the spike proteins will have a major role in the disease of SARS-CoV infected patients. Therefore, the central objective of this project is to identify and characterize regions of the SARS spike proteins that confer the ability to infect both animals and humans. As part of this objective, we will identify host cell receptors used by SARS-CoV, using soluble spike proteins as detection reagents. As receptors are found, we will proceed by determining whether spike polymorphisms alter affinities for animal or human receptor homologs, as this may explain animal-to-human virus transmissions. We will focus on relevant human airway cells and will identify both cellular and viral determinants of spike-mediated syncytial formation, as syncytia are a recognized hallmark of coronavirus cytopathology. Coronaviruses can accommodate many adaptive mutations in their spike proteins, and we hypothesize that xenotropic and pathogenic SARS-CoVs are distinguished as a subset of these mutant forms. We will advance our understanding of SARS-CoV epidemiology and pathogenesis by identifying these variants and characterizing their receptor binding and syncytium inducing properties.